(19) TZZ ¥6B_T (11) EP 2 222 636 B1 (12) EUROPEAN PATENT SPECIFICATION (45) Date of publication and mention (51) Int Cl.: of the grant of the patent: C07D 207/08 (2006.01) C07D 207/09 (2006.01) 10.04.2013 Bulletin 2013/15 C07D 498/04 (2006.01) A61K 31/402 (2006.01) A61P 5/26 (2006.01) (21) Application number: 08865188.0 (86) International application number: (22) Date of filing: 12.12.2008 PCT/US2008/013657 (87) International publication number: WO 2009/082437 (02.07.2009 Gazette 2009/27) (54) SELECTIVE ANDROGEN RECEPTOR MODULATORS (SARMS) AND USES THEREOF SELEKTIVE ANDROGENREZEPTORMODULATOREN (SARMS) UND IHRE VERWENDUNG MODULATEURS SÉLECTIFS DU RÉCEPTEUR ANDROGÈNE (SARM) ET LEURS UTILISATIONS (84) Designated Contracting States: (74) Representative: Baldock, Sharon Claire AT BE BG CH CY CZ DE DK EE ES FI FR GB GR Boult Wade Tennant HR HU IE IS IT LI LT LU LV MC MT NL NO PL PT Verulam Gardens RO SE SI SK TR 70 Gray’s Inn Road Designated Extension States: London WC1X 8BT (GB) AL BA MK RS (56) References cited: (30) Priority: 21.12.2007 US 8731 P WO-A-02/068427 WO-A-03/090672 WO-A-2005/090282 WO-A-2006/124447 (43) Date of publication of application: WO-A-2007/015567 01.09.2010 Bulletin 2010/35 • HIGUCHI ET AL: "Potent, nonsteroidal selective (60) Divisional application: androgen receptor modulators (SARMs) based 12168231.4 / 2 489 656 on 8H-[1,4]oxazino[2,3-f]quinolin-8-ones" BIOORGANIC & MEDICINAL CHEMISTRY (73) Proprietor: Ligand Pharmaceuticals Inc. LETTERS, PERGAMON, ELSEVIER SCIENCE, San Diego, CA 92037 (US) GB, vol. 17, no. 19, 14 September 2007 (2007-09-14), pages 5442-5446, XP022249734 (72) Inventor: ZHI, Lin ISSN: 0960-894X San Diego, CA 92130 (US) Remarks: Thefile contains technical information submitted after the application was filed and not included in this specification Note: Within nine months of the publication of the mention of the grant of the European patent in the European Patent Bulletin, any person may give notice to the European Patent Office of opposition to that patent, in accordance with the Implementing Regulations. Notice of opposition shall not be deemed to have been filed until the opposition fee has been paid. (Art. 99(1) European Patent Convention). EP 2 222 636 B1 Printed by Jouve, 75001 PARIS (FR) EP 2 222 636 B1 Description Related Applications 5 [0001] Benefit of priority is claimed to U.S. Provisional Patent Application Serial No. 61/008,731, to Lin Zhi, filed on December 21, 2007, entitled "SELECTIVE ANDROGEN RECEPTOR MODULATORS (SARMs) AND USES THEREOF." Field 10 [0002] Provided herein are selective androgen receptor modulator (SARM) compounds that bind to androgen receptors and/or modulate activity of androgen receptors, and to methods for making and using such compounds. Also provided are compositions including such compounds and methods for making and using such compositions. Background 15 [0003] Certain intracellular receptors (IRs) have been shown to regulate transcription of certain genes (e.g., see R. M. Evans, Science 240:889 (1988)). Certain of such IRs are steroid receptors, such as androgen receptors, estrogen receptors, mineralocorticoid receptors, and progesterone receptors. Gene regulation by such receptors typically involves binding of an IR by a ligand. 20 [0004] In certain instances, a ligand binds to an IR, forming a receptor/ligand complex. Such a receptor/ligand complex can then translocate to the nucleus of a cell, where it binds to the DNA of one or more gene regulatory regions. Once bound to the DNA of a particular gene regulatory region, a receptor/ ligand complex can modulate the production of the protein encoded by that particular gene. In certain instances, an androgen receptor/ ligand complex regulates expression of certain proteins. In certain instances, an androgen receptor/ligand complex can interact directly with the DNA of a 25 particular gene regulatory region or with other transcription factors. In certain instances, such interactions result in modulation of transcriptional activation. [0005] Androgen therapy has been used to treat a variety of male disorders such as reproductive disorders and primary or secondary male hypogonadism. A number of natural or synthetic AR agonists have been investigated for the treatment of musculoskeletal disorders, such as bone disease, hematopoietic disorders, neuromuscular disease, rheumatological 30 disease, wasting disease, and for hormone replacement therapy (HRT), such as female androgen deficiency. In addition, AR antagonists, such as flutamide and bicalutamide, are used to treat prostate cancer. The effectiveness of known modulators of steroid receptors is often tempered by their undesired side-effect profile, particularly during long-term administration. For example, potential side effects of androgen therapy for women include acne, weight gain, excess facial and body hair, permanent lowering of the voice, and adverse lipid changes. In men, adverse effects can include 35 disordered sleep and breathing, polycythemia, and repression of high density lipoprotein. Thus there is a need for compounds that do not exhibit the adverse side-effects. It is among the objects herein to provide such compounds that modulate the activity of androgen receptor. Summary 40 [0006] Compounds for use in compositions and methods for modulating the activity of androgen receptor are provided. The compounds provided herein are non-steroidal Selective Androgen Receptor Modulators or SARMs. In particular, non-steroidal SARMs display therapeutic benefit but generally do not display adverse androgenic effects, such as prostate enlargement, acne, hirsutism, virilization and masculinization. The compounds selectively modulate (agonize or antag- 45 onize) the function of the AR, such as in a tissue- selective manner, to produce the effects of androgens without or with reduced negative or undesired androgenic properties. Among the compounds provided herein are agonists of androgen receptor. Among the compounds provided herein are antagonists of androgen receptor. Among the compounds provided herein are androgen receptor partial agonists. [0007] Among the compounds provided herein are tissue specific selective androgen receptor modulators. They can 50 be used for oral testosterone replacement therapy. Compounds provided herein display agonist activity with EC 50 values generally less than 1 micromolar. Compounds provided herein display antagonist activity with IC 50 values generally less than 2 micromolar. SARMs provided herein generally target anabolic tissue, such as connective tissue, including bone and muscle, and can be used to increase the mass ofa connective tissue in a subject and to reverse connective tissue loss in a subject. Among the disorders that can be treated are muscle wasting, cachexia, frailty and osteoporosis and 55 other muscle and bone disorders, including those enumerated below. [0008] Compounds provided herein have a structure of Formula I: 2 EP 2 222 636 B1 5 10 1 2 3 where R is CF3, F, or Cl; R hydrogen or methyl; R is hydrogen or methyl; also described are compounds having a 4 structure of Formula II or Formula III, where R is halogen or lower haloalkyl, particularly CF 3 or halogen, and in particular 5 Cl or CF3; and R is lower alkyl or lower haloalkyl, particularly C1 to C4 alkyl or C1 to C4 haloalkyl, and in particular methyl, ethyl or CF3. Also provided are a pharmaceutically acceptable salt, ester or an acetate, formate or benzoate derivative of an alcohol functional group of compound of formula I. 15 [0009] In some embodiments, the compounds provided herein exhibit tissue selective androgen receptor agonist activity. In some embodiments, the compounds provided herein exhibit tissue selective androgen receptor antagonist activity. also described herein are androgen receptor selective binding compounds. [0010] Compounds provided herein are effective for treating one or more androgen receptor mediated diseases or conditions. Such conditions and diseases include those caused by androgen deficiency and/or those that can be amel- 20 iorated by androgen administration. In certain embodiments, compounds provided herein are effective for treating one or more diseases or conditions responsive to an androgen receptor agonist. In certain embodiments, compounds provided herein are effective in treating one or more conditions whose etiology involves hypoactivity or subsensitivity of androgen receptor. In other embodiments, compounds provided herein are effective for treating one or more diseases or conditions responsive to an androgen receptor antagonist. In other embodiments, compounds provided herein are effective in 25 treating one or more conditions whose etiology involves hyperactivity of androgen receptor. [0011] In some tissues, the compounds provided herein can exhibit AR agonist activity and can be used to treat conditions that are caused by androgen deficiency or hypoactivity or subsensitivity of androgen receptor, or that can be ameliorated by androgen replacement or are responsive to treatment with an AR agonist. Such conditions, include, but not limited to, aging skin; Alzheimer’s disease; anemias, such as for example, aplastic anemia; anorexia; arthritis, 30 including inflammatory arthritis, rheumatoid arthritis, osteoarthritis and gout; arteriosclerosis; atherosclerosis; bone dis- ease, including metastatic bone disease; bone damage or fracture, such as by accelerating bone fracture repair and/or stimulation of osteoblasts and/or stimulation of bone remodeling and/or stimulation of cartilage growth; distraction